Compound preparation for treating helicobacter pylori and preparation method thereof

Abstract

The invention discloses a compound medicinal preparation and a preparation method thereof, wherein the compound medicinal preparation consists of Vonoprasan or medicinal salt thereof, amoxicillin and levornidazole or levornidazole phosphate. The Vonoprazan is a novel potassium ion competitive acid blocker, and the compound preparation is used for treating gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, and helicobacter pylori infection and helicobacter pylori infection gastritis in the stomach after early gastric cancer endoscopic therapy. According to the compound preparation, the cure rate of helicobacter pylori can be increased, the drug resistance can be reduced, and a better treatment choice is provided for clinical patients.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a compound preparation consisting of vonoprazan and its soluble salt, amoxicillin and levornidazole or levornidazole phosphate and a preparation method thereof. Background Art

[0002] Helicobacter pylori (Hp) is a Gram-negative, microaerobic spiral bacterium that is closely related to human gastrointestinal diseases. Studies have shown that H. pylori infection can cause chronic gastritis and promote the occurrence and development of a variety of digestive tract diseases, such as indigestion, peptic ulcers and gastric cancer. Among them, the most serious consequence of H. pylori infection is the induction of gastric cancer. Studies have shown that 90% of gastric cancer cases worldwide are closely related to H. pylori infection. According to statistics from the World Health Organization, gastric cancer is the fourth most common cancer in the world and the second most deadly, causing nearly 750,000 deaths each year. Therefore, H. pylori infection seriously threatens human health and causes huge economic and social losses. The prevention and treatment of H. pylori infection has great applied research value.

[0003] The treatment of Helicobacter pylori is completely different from other microbial infections. Since it is extremely difficult to isolate and culture the bacteria, doctors mainly rely on clinical experience and statistical results of large health institutions (such as the World Health Organization) to develop anti-infection plans. At present, the World Health Organization recommends a triple therapy based on clarithromycin for the treatment of Helicobacter pylori infection: a proton pump inhibitor, clarithromycin, combined with amoxicillin or metronidazole or tinidazole for 14 days. However, the effectiveness of anti-Helicobacter pylori treatment has been declining in recent years, and the success rate of anti-Helicobacter pylori treatment in China has been less than 80%. The failure of anti-Helicobacter pylori infection treatment is mainly related to the increase in the bacteria's resistance to antibiotics. Studies have found that the resistance rate of Helicobacter pylori to clarithromycin, metronidazole and levofloxacin in people infected in Jiangsu and Zhejiang provinces in my country is 21.5%, 95.4% and 20.6%, and the proportion of resistance to three commonly used clinical antibiotics is as high as 7.6%. Due to the extensive resistance of Helicobacter pylori to antibiotics in my country, the existing treatment options cannot effectively control Helicobacter pylori infection in my country. Therefore, developing new drugs, preparations and materials to address the problem of multidrug-resistant Helicobacter pylori is of great significance to improving the health level of our nation.

[0004] Currently, proton pump inhibitors (PPIs) have been widely prescribed for the first-line treatment of acid-related diseases. However, PPIs do not always provide adequate efficacy, and the inhibitory effect on gastric acid secretion may vary from person to person. This is because CYP-2C19, a protein involved in PPI metabolism, has genetic polymorphisms in its encoding gene in different individuals. However, vonoprazan is not mainly metabolized by CYP2C19, and vonoprazan's inhibitory effect on the proton pump does not require acid activation. The drug enters the stomach at high concentrations and can produce the maximum inhibitory effect at the first dose, and this effect can last for 24 hours.

[0005] Vonoprazan Fumarate (TAK-38) was jointly developed by Takeda Pharmaceuticals and Otsuka Pharmaceuticals and was approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on December 26, 2014. The specific structural formula is as follows:

[0006] Vonoprazan fumarate is a new type of potassium ion (K + Competitive acid blockers (P-CABs) can competitively inhibit K secretion in the final step of gastric acid secretion by gastric parietal cells. + With H + -K + -ATPase (proton pump) binding effect, resulting in a strong and lasting inhibition of gastric acid secretion. This drug is suitable for gastric ulcer, duodenal ulcer, reflux esophagitis, erosive esophagitis, gastroesophageal reflux disease, Helicobacter infection and peptic ulcer.

[0007] Currently, the combination packaged medicine of vonopion fumarate, amoxicillin capsules and metronidazole tablets (VONOPION®Pack) and the combination packaged medicine of vonopion fumarate, amoxicillin capsules and metronidazole tablets (VONOSAP® Pack 400&800) jointly developed by Takeda Pharmaceutical (Takeda) and Otsuka Pharmaceutical (Otsuka) for the treatment of Helicobacter pylori were approved for marketing by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in June 2016.

[0008] Amoxicillin hydrate acts by inhibiting bacterial cell wall synthesis, while vonoprazan does not require acid activation and inhibits H in a reversible and potassium-competitive manner. + , K +-ATPase. Vonoprazan is strongly alkaline and stays in the acid-producing sites of gastric parietal cells for a long time, inhibiting the production of gastric acid. Vonoprazan does not show anti-Helicobacter pylori activity or Helicobacter pylori urease inhibitory activity. Metronidazole is reduced and converted into a nitroso compound (R-NO) through a reaction of the nitroreductase system in Helicobacter pylori. This R-NO shows a bactericidal effect against Helicobacter pylori. In addition, the hydroxyl radicals produced during the reaction will cleave DNA, resulting in an unstable DNA helical structure. The effect of vonoprazan in triple therapy with amoxicillin and metronidazole is believed to be to enhance the antibacterial activity of amoxicillin and metronidazole by increasing gastric pH.

[0009] The vonoprazan fumarate pharmaceutical composition currently on the market in Japan is used to treat Helicobacter pylori, and the three are taken separately. Patient compliance is poor and drug resistance is high. It is necessary to provide a new method to solve the above problems.

[0010] Therefore, we found in the study that the combination of levornidazole or levornidazole phosphate with vonoprazan fumarate and amoxicillin has a strong inhibitory effect on Helicobacter pylori strains and low drug resistance. It is a better drug combination for treating Helicobacter pylori infection. Summary of the invention

[0011] In view of the deficiencies in the prior art, the object of the present invention is to provide a compound preparation containing vonoprazan fumarate, amoxicillin and levornidazole or levornidazole phosphate and a preparation method thereof. Vonoprazan fumarate enhances the antibacterial activity of amoxicillin and levornidazole or levornidazole phosphate, simplifies the medication regimen, improves the patient's medication compliance, improves the clinical cure rate and reduces drug resistance.

[0012] A compound preparation consisting of vonoprazan or a pharmaceutically acceptable salt thereof, amoxicillin, levornidazole or levornidazole phosphate; The pharmaceutically acceptable salt of vonoprazan is selected from fumarate, succinate, maleate, malate or tartrate.

[0013] When the compound preparation is a capsule, the main component is 40-60%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8%, the lubricant is 0.5%-2% and the stabilizer is 0.1%-0.5% by weight.

[0014] When the compound preparation is a tablet, the main component is 40-60%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8%, the glidant is 0.5%-2%, the lubricant is 0.5%-2% and the stabilizer is 0.1%-0.5% by weight.

[0015] When the compound preparation is a granule, the main component is 10-50%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8% and the stabilizer is 0.5%-2%.

[0016] When the compound preparation is an oral dry suspension, the main component is 10-50%, the filler is 2-8%, the stabilizer is 0.02-0.05%, the disintegrant is 2-10%, the suspending agent is 0.5%-2% and the flavoring agent is 0.5%-2%.

[0017] The filler is selected from one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose, mannitol or a co-processed product of microcrystalline cellulose and mannitol; The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, microcrystalline cellulose or low-substituted hydroxypropyl cellulose; The binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, sodium carboxymethyl cellulose, guar gum, xanthan gum, gelatin or gum arabic; The glidant is silicon dioxide, colloidal silicon dioxide; The suspending agent is selected from one or more of silica bentonite, magnesium aluminum silicate, colloidal microcrystalline cellulose, colloidal silicon dioxide, microcrystalline cellulose colloidal silicon dioxide co-processed product, hypromellose, and hydroxyethyl cellulose. Among them, colloidal cellulose sodium is a composite of microcrystalline cellulose and sodium carboxymethyl cellulose, and microcrystalline cellulose colloidal silicon dioxide co-processed product is prepared by mixing and drying microcrystalline cellulose and colloidal silicon dioxide in water.

[0018] The lubricant is selected from one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate or glyceryl behenate; The stabilizer is selected from fumaric acid; The flavoring agent is selected from sucralose, sucrose, fructose, aspartame, saccharin sodium, glycerol, sorbitol, and mannitol; Another object of the present invention is to provide a method for preparing the above-mentioned compound preparation, and to prepare corresponding preparations according to the prescriptions.

[0019] Furthermore, when the compound preparation is a capsule, the preparation method thereof comprises the following steps: Granulation: Dissolve the stabilizer and binder in purified water and stir to prepare a binder solution; add the active ingredient, filler, and disintegrant into a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. Granulation: The dry granules are granulated by a granulator; Total mixing: Add the dry granules, disintegrant and lubricant into a three-dimensional mixer and mix well; Filling: Filling the total mixed granules into capsule shells to obtain the capsules.

[0020] Furthermore, when the compound preparation is a tablet, the preparation method thereof comprises the following steps: Granulation: Dissolve the stabilizer and binder in purified water and stir to prepare a binder solution; add the active ingredient, filler, and disintegrant into a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. Granulation: The dry granules are granulated by a granulator; Total mixing: Add the dry granules, disintegrant and lubricant into a three-dimensional mixer and mix well; Tableting: The mixed powder is placed on a tablet press to obtain the tablets.

[0021] Furthermore, when the compound preparation is a granule, its preparation method comprises the following steps: The main components are crushed to a particle size range of 1 to 10 um for D50 and 5 to 30 um for D90; Weigh the prescribed amount of filler, disintegrant, stabilizer, and flavoring agent respectively; Weigh the prescribed amount of purified water, add the prescribed amount of stabilizer and binder under high-speed dispersion to prepare a wetting agent for use; The active ingredient, filler, disintegrant and flavoring agent are pre-mixed in a wet mixing granulator, and then the prepared wetting agent is added to obtain a soft material, which is granulated and then transferred to a fluidized bed for drying; After drying, the granules are granulated again; The granules are mixed with essence to obtain the granules.

[0022] Furthermore, when the compound preparation is an oral dry suspension, its preparation method comprises the following steps: The active ingredient, the stabilizer and the suspending agent are mixed to obtain a dispersion 1; Weigh the filler and the dispersion 1 after passing through a 30-mesh sieve, place them in a main mixing barrel and mix them evenly to obtain a mixed powder 2; The mixed powder 2 is placed in a dry granulator for dry granulation and then pulverized through a 0.3 mm sieve to obtain dry granules 3; Put the dry granules 3 and the flavoring agent into a main mixing barrel and mix them evenly to obtain mixed granules 4; The mixed granules 4 are packed into a bag to obtain the oral dry suspension.

[0023] The compound preparations of the present invention are all the most commonly used preparation processes for oral solid preparations, and the excipients used are also conventional excipients. The entire production process is smooth, easy to operate, and has good reproducibility, and is suitable for commercial production.

[0024] The compound preparation of the present invention is generally used for gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection of the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori infectious gastritis. Amoxicillin hydrate is effective by inhibiting bacterial cell wall synthesis. Vonoprazan fumarate does not require acid activation and inhibits H + , K + -ATPase in a competitive style with reversible potassium ions. Bono Plazan inhibits gastric acid production and remains essential for a long time in the acid-producing sites of gastric parietal cells. Vonoplasmin fumarate has no anti-Helicobacter pylori activity and Helicobacter pylori inhibitory activity. Levoornidazole or levornidazole phosphate obtains reduction through the reaction of the nitroreductase system in Helicobacter pylori and is converted into a nitro compound (R-NO). R-NO shows a bactericidal effect against Helicobacter pylori. In addition, the hydroxyl radical generated during the reaction cuts DNA, resulting in the destabilization of the DNA helical structure. The effect of vonoplasmin fumarate in a three-dose treatment with amoxicillin and levornidazole or levornidazole phosphate, by increasing the gastric pH, the antibacterial activity of amoxicillin and levornidazole or levornidazole phosphate is considered to be increased. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further described in detail below in conjunction with specific embodiments, but it is not intended to limit the protection scope of the present invention.

[0026] Examples 1 to 4: Preparation of capsules Table 1 Prescription composition of capsules

[0027] Preparation process: Raw material pretreatment: crush the main ingredients to a particle size range of 1-10um for D50 and 5-30um for D90; Granulation: dissolve fumaric acid and binder in purified water and stir to prepare a binder solution; add vonoprazan fumarate, amoxicillin and levornidazole or levornidazole phosphate, filler and disintegrant into a wet granulator, mix for 5 minutes at a stirring paddle speed of 300 rpm and a cutting knife speed of 500 rpm; spray the hydroxypropyl cellulose aqueous solution into the mixture at a stirring paddle speed of 200 rpm and a cutting knife speed of 500 rpm, and add the mixture in about 8 minutes; granulate for 2 minutes at a stirring paddle speed of 250 rpm and a cutting knife speed of 1200 rpm; discharge, wet granulate the granulator with a 3×3 mm screen and a rotation speed of 400 rpm.

[0028] Drying: Add wet granules into the fluidized bed, feed air at 60℃ and 30Hz, dry. When the material temperature reaches 40℃, take samples to measure the moisture content. When the moisture content is lower than 2.0%, stop heating and cool the material for discharge.

[0029] Granulation: Granulation machine screen diameter 1mm, rotation speed 400rpm, granulation.

[0030] Total mixing: Add the granules and magnesium stearate into a three-dimensional mixer at a mixing speed of 30 Hz for 10 min.

[0031] Filling: Filling the total mixed granules into capsule shells to obtain the capsules.

[0032] Examples 5 to 8: Preparation of tablets Table 2 Prescription composition of tablets

[0033] Preparation process: Raw material pretreatment: crush the main ingredients to a particle size range of 1-10um for D50 and 5-30um for D90; Granulation: dissolve fumaric acid and binder in purified water and stir to prepare a binder solution; add vonoprazan fumarate, amoxicillin and levornidazole or levornidazole phosphate, filler and disintegrant into a wet granulator, stir at a paddle speed of 300 rpm and a cutter speed of 500 rpm, and mix for 5 minutes; stir at a paddle speed of 200 rpm and a cutter speed of 500 rpm, spray into the hydroxypropyl methylcellulose solution by atomization, and add it in about 8 minutes; stir at a paddle speed of 250 rpm and a cutter speed of 1200 rpm, and granulate for 2 minutes; discharge, granulate with a granulator screen of 3×3 mm, rotate at a speed of 400 rpm, and wet granulate.

[0034] Drying: Add wet granules into the fluidized bed, feed air at 60℃ and 30Hz, dry. When the material temperature reaches 40℃, take samples to measure the moisture content. When the moisture content is lower than 2.0%, stop heating and cool the material for discharge.

[0035] Granulation: Granulation machine screen diameter 1mm, rotation speed 400rpm, granulation.

[0036] Total mixing: Add the granules and magnesium stearate into a three-dimensional mixer at a mixing speed of 30 Hz for 10 min.

[0037] Tableting: The total mixed granules are placed in a tablet press for tableting to obtain the tablets.

[0038] Examples 9-12: Preparation of granules Table 3 Prescription composition of granules

[0039] Preparation process: Pretreatment of raw materials and auxiliary materials: crush the main ingredients to a particle size range of 1-10um for D50 and 5-30um for D90; pass sucrose, dextrin and sodium carboxymethyl starch through an 80-mesh sieve; Preparation of adhesive: Prepare 5% guar gum aqueous solution; Granulation and drying: After the three APIs and other excipients are mixed, a binder is added to obtain a soft material, which is then granulated and transferred to a fluidized bed for drying; Whole grain: After drying, the granules are then whole grained; Total mixing: Mix the whole granules with sweet orange essence; Filling: The total mixed granules are bagged to obtain the granules.

[0040] Examples 13-16: Preparation of dry suspension Table 4 Prescription composition of dry suspension

[0041] Preparation process: Sucrose was crushed, and sucrose, aspartame, colloidal silicon dioxide, xanthan gum, and hydroxypropyl methylcellulose were dried at 80° C. at normal pressure for 3 hours to obtain dispersion 1; The dried dispersion 1 and the main drug are placed in a main mixing barrel and mixed to obtain a mixed powder 2; The mixed powder 2 is placed in a dry granulator for dry granulation and then pulverized through a 0.3 mm sieve to obtain dry granules 3; The dry granules 3 and the flavoring agent are placed in a main mixing barrel and mixed to obtain mixed granules 4; The mixed granules 4 are packed into a bag to obtain the oral dry suspension; Example 17: Antibacterial Activity Against Helicobacter pylori (In Vitro) (1) Single drug sensitivity test Agar dilution method H.pylori In vitro sensitivity to vonoprazan fumarate, amoxicillin, clarithromycin, metronidazole, and levornidazole was tested in accordance with the CLSIM7-A7 document. H.pylori The minimum inhibitory concentration (MIC) of antimicrobial drugs refers to the "Criteria for Determination of Antimicrobial Efficacy Tests" and CLSIM100-S17 documents, with MIC of vonoprazan fumarate ≥ 64 μg / ml, MIC of levonidazole or levonidazole phosphate ≥ 2 μg / ml, MIC of clarithromycin ≥ 2 μg / ml, MIC of amoxicillin ≥ 8 μg / ml, and MIC of metronidazole ≥ 8 μg / ml as the standard. H.pylori Resistance to antimicrobial drugs.

[0042] (2) Combined drug sensitivity test In filtering out H.pylori Based on sensitive antibacterial drugs, the drug sensitivity test of the combination of vonoprazan fumarate and 2 antibacterial drugs was carried out using the "checkerboard method" respectively, and the antibacterial effect of the combination of vonoprazan fumarate and 2 antibacterial drugs was evaluated by calculating the fractional inhibitory concentration (FIC). Judgment criteria: FIC ≤ 0.5 indicates that the combination of vonoprazan fumarate and 2 antibacterial drugs has a synergistic effect; 0.5 < FIC ≤ 1 indicates that the combination of vonoprazan fumarate and 2 antibacterial drugs has an additive effect; 1 < FIC ≤ 2 indicates that the combination of vonoprazan fumarate and 2 antibacterial drugs has no associated effect.

[0043] (3)In vitro antibacterial effect analysis of different drugs against H.pylori 90 strains H.pylori The drug resistance rates of different drugs from high to low were clarithromycin 52.2%, metronidazole 22.2%, amoxicillin 8.9%, and levornidazole 3.3%. H.pylori The drug resistance rate to clarithromycin was the highest, and the drug resistance rate to levornidazole was the lowest. The results are shown in Table 5.

[0044] Table 5 In vitro antibacterial effect of different drugs against H.pylori

[0045] (4)Analysis of the in vitro antibacterial effect of triple-drug combination of antibacterial drugs against Hp The synergistic inhibitory effect of vonoprazan combined with amoxicillin and clarithromycin, vonoprazan combined with amoxicillin and levornidazole or levornidazole phosphate is the strongest. Vonoprazan combined with metronidazole and amoxicillin, vonoprazan combined with metronidazole and levornidazole has a synergistic inhibitory effect. Vonoprazan combined with clarithromycin and levornidazole or levornidazole phosphate has an additive antibacterial effect, while the inhibitory effect of vonoprazan combined with clarithromycin and metronidazole has no association. The results are shown in Table 6.

[0046] Table 6 FIC analysis of different combinations of antibacterial drugs against Hp

[0047] The synergistic inhibitory effect of vonoprazan combined with amoxicillin and clarithromycin, vonoprazan combined with amoxicillin and levornidazole or levornidazole phosphate is the strongest. Vonoprazan combined with metronidazole and amoxicillin, vonoprazan combined with metronidazole and levornidazole has a synergistic inhibitory effect. Vonoprazan combined with clarithromycin and levornidazole or levornidazole phosphate has an additive antibacterial effect, while the inhibitory effect of vonoprazan combined with clarithromycin and metronidazole has no association.

[0048] Experimental Example 1 Antibacterial Experiment of Compound Preparation against Helicobacter pylori Helicobacter pylori strain (ATCC26695) was inoculated into a culture medium (Columbia blood agar containing 7% defibrinated sheep blood) for culture.

[0049] The cultured Helicobacter pylori strain (ATCC26695) was collected and prepared into 3.0×10 8 cfu / mL of bacterial suspension was prepared with Helicobacter pylori liquid culture medium containing different concentrations of the compound preparation (Examples 1-16), and placed in a 37°C incubator. After culturing for 72 hours, the minimum inhibitory concentration (MIC) of the compound preparation was read, which was 6.4 μg / mL.

[0050] This indicates that the compound preparation of the present invention has a strong inhibitory effect on Helicobacter pylori.

[0051] Experimental Example 2 Antibacterial Experiment of the Compound Preparation on Mice Infected with Helicobacter pylori 200 male C57BL / 6 mice were randomly divided into a blank control group, a positive control group (comparative sample 1 (prepared according to the sample of Example 4 of Publication No. CN110354125 A), comparative sample 2 (prepared according to the sample of Example 1 of Authorization Announcement No. CN117398360 B), comparative sample 3 (VONOPION® Pack combined packaged drug)), and a test group. The drugs were administered for 7 days in total; the mice after administration were all killed, and the gastric tissues were taken out for RUT experiment and WS staining. If the RUT and WS staining results were negative, it was judged that Helicobacter pylori was eradicated successfully. The eradication rate of each group was calculated. The results are shown in Table 7.

[0052] Table 7 shows the antibacterial test results of each group on mice infected with Helicobacter pylori (n=10)

[0053] The above results show that after 7 days of treatment, the eradication rate of the compound capsule provided by the present invention is better than that of the positive control group and the blank group, and the eradication rate can reach 100%. It can be concluded that the compound capsule provided by the present invention has a good eradication rate for Helicobacter pylori and has better efficacy than the publicly disclosed technical solutions.

[0054] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. A pharmaceutical compound preparation, characterized in that: The compound preparation is composed of vonoprazan or a pharmaceutically acceptable salt thereof, amoxicillin, levornidazole or levornidazole phosphate and pharmaceutically acceptable excipients; the structural formulas of vonoprazan, amoxicillin, levornidazole and levornidazole phosphate are as follows: Vonolazen Amoxicillin Levoornidazole Levotronidazole phosphate.

2. The pharmaceutical compound preparation according to claim 1, characterized in that: The pharmaceutically acceptable salt of vonoprazan is selected from fumarate, succinate, maleate, malate or tartrate.

3. The pharmaceutical compound preparation according to claim 1, characterized in that: The compound preparation can be selected as capsules, tablets, granules or oral dry suspensions; When the compound preparation is a capsule, the main component is 40-60%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8%, the lubricant is 0.5%-2% and the stabilizer is 0.1%-0.5% by weight. When the compound preparation is a tablet, by weight percentage, the main component is 40-60%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8%, the glidant is 0.5%-2%, the lubricant is 0.5%-2% and the stabilizer is 0.1%-0.5%; When the compound preparation is a granule, the main component is 10-50%, the filler is 20-30%, the disintegrant is 1-5%, the binder is 2-8% and the stabilizer is 0.5%-2% by weight; When the compound preparation is an oral dry suspension, the main component is 10-50%, the filler is 2-8%, the stabilizer is 0.02-0.05%, the disintegrant is 2-10%, the suspending agent is 0.5%-2% and the flavoring agent is 0.5%-2%.

4. The compound preparation according to claim 2, characterized in that: The filler is selected from one or more of microcrystalline cellulose, lactose, corn starch, silicified microcrystalline cellulose, mannitol or a co-processed product of microcrystalline cellulose and mannitol; The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, microcrystalline cellulose or low-substituted hydroxypropyl cellulose; The binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, sodium carboxymethyl cellulose, guar gum, xanthan gum, gelatin or gum arabic; The glidant is silicon dioxide, colloidal silicon dioxide; The suspending agent is selected from one or more of silica bentonite, magnesium aluminum silicate, colloidal microcrystalline cellulose, colloidal silicon dioxide, microcrystalline cellulose colloidal silicon dioxide co-processed product, hypromellose, and hydroxyethyl cellulose; The colloidal cellulose sodium is a composite of microcrystalline cellulose and sodium carboxymethyl cellulose, and the microcrystalline cellulose colloidal silicon dioxide co-processed product is prepared by mixing and drying microcrystalline cellulose and colloidal silicon dioxide in water; The lubricant is selected from one or more of stearic acid, zinc stearate, magnesium stearate, polyethylene glycol, sodium stearyl fumarate or glyceryl behenate; The stabilizer is selected from fumaric acid; The flavoring agent is selected from sucralose, sucrose, fructose, aspartame, saccharin sodium, glycerol, sorbitol, and mannitol.

5. The pharmaceutical compound preparation according to claim 1, characterized in that: The preparation method of the compound preparation is as follows: When the compound preparation is a capsule, the preparation method thereof comprises the following steps: Granulation: Dissolve the stabilizer and binder in purified water and stir to prepare a binder solution; add the active ingredient, filler, and disintegrant into a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. Granulation: The dry granules are granulated by a granulator; Total mixing: Add the dry granules, disintegrant and lubricant into a three-dimensional mixer and mix well; Filling: filling the total mixed granules into the capsule shell to obtain the capsule; When the compound preparation is a tablet, the preparation method thereof comprises the following steps: Granulation: Dissolve the stabilizer and binder in purified water and stir to prepare a binder solution; add the active ingredient, filler, and disintegrant into a fluidized bed granulator, spray the binder solution into the fluidized bed granulator, and granulate; Drying: Dry the granules in a fluidized bed granulator. When the moisture content is less than 3%, stop heating and cool the granules. Granulation: The dry granules are granulated by a granulator; Total mixing: Add the dry granules, disintegrant and lubricant into a three-dimensional mixer and mix well; Tableting: the mixed powder is placed in a tablet press to obtain the tablet; When the compound preparation is a granule, the preparation method thereof comprises the following steps: The main components are crushed to a particle size range of 1 to 10 um for D50 and 5 to 30 um for D90; Weigh the prescribed amount of filler, disintegrant, stabilizer, and flavoring agent respectively; Weigh the prescribed amount of purified water, add the prescribed amount of stabilizer and binder under high-speed dispersion to prepare a wetting agent for use; The active ingredient, filler, disintegrant and flavoring agent are pre-mixed in a wet mixing granulator, and then the prepared wetting agent is added to obtain a soft material, which is granulated and then transferred to a fluidized bed for drying; After drying, the granules are granulated again; The granules are mixed with the essence to obtain the granules; When the compound preparation is an oral dry suspension, the preparation method thereof comprises the following steps: The active ingredient, the stabilizer and the suspending agent are mixed to obtain a dispersion 1; Weigh the filler and the dispersion 1 after passing through a 30-mesh sieve, place them in a main mixing barrel and mix them evenly to obtain a mixed powder 2; The mixed powder 2 is placed in a dry granulator for dry granulation and then pulverized through a 0.3 mm sieve to obtain dry granules 3; Put the dry granules 3 and the flavoring agent into a main mixing barrel and mix them evenly to obtain mixed granules 4; The mixed granules 4 are packed into a bag to obtain the oral dry suspension.

6. The pharmaceutical compound preparation according to claim 1, characterized in that: Used in the preparation of medicines for treating gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, Helicobacter pylori infection in the stomach after endoscopic treatment of early gastric cancer, and Helicobacter pylori infection gastritis.

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